Connective Tissue/Skeletal Dysplasia/Collagenopathies Flashcards
List the disorders of fibrillin-TGFbeta pathway.
Marfan Syndrome
Loeys-Deitz Syndrome
List the disorders of collagen production and assembly.
Ehlers Danlos Syndrome
Osteogenesis Imperfecta
Stickler Syndrome
What is Marfan Syndrome?
AD
mutations in FBN1 gene with complete penetrance (though normally age related)
25% spontaneous mutations
What is the 2010 Ghent criteria?
used to diagnose Marfan Syndrome without family history Ao (Z>2) + Ectopia Lentis Ao (Z>2) + FBN1 mutation Ao (Z>2) + Systemic score (>7 points) Ectopia Lents + FBN1 known Ao with family history one of (Ectopia lentis, systemic score >7 points, Ao (Z>2 above 20, >3 below 20yo)
What contributes to the Marfan Syndrome systemic score?
pectus excavotum/pigeon (1-2 points) wrist/thumb signs (1-3 points) pneumothorax (2 points) armspan/height or US/LS (1) scoliosis/kyphosis (1) myopia (>3 dpts) facial features (1 each) dural ectasia (2) food deformity/pes planus (1-2) elbow extension decreased (1) skin striae (1) protrusio acetabulae (2)
What are the most common phenotypes associated with Marfan syndrome?
ectopia lentis (bilateral, symmetrical, and superotemporal/upsloping)
other ocular abnormalities (myopia, retinal detachment, glaucoma)
progressive aortic dilation
other cardiac (MVP, MR, TR, enlarged pulmonary artery)
dural ectasia
dolichostenomelia
arachnodactyly
What is Neonatal Marfan Syndrome?
severe early presentation of symptoms
50% mortality by 1st year (due to severe mitral valve regulation and heart failure)
most de novo mutations (exons 24-32)
What fetal US findings are associated with Neonatal Marfan Syndrome?
arachnodactyly joint contractures AV valve insufficiency worsening cardiomegally dilated pulmonary and aortic roots
What other conditions have FBN1 mutations but do not meet the Ghent criteria?
MASS phenotype
Mitral valve prolapse
Familial ectopia lentis
Thoracic aortic aneurysm
How is Marfan Syndrome managed?
restriction of contact/competitive sports and isometric exercise
surveillance (annual or more frequent CT/MRA in adults for cardiology to assess aorta size)
medications (beta blockers; losartan)
surgical repair
avoide LASIK and SCUBA procedures
How is Marfan Syndrome managed in females who are or are planning to become pregnant?
pre-pregnancy ECHO with monitoring every 2-3 months
aortic diameter <40mm and minimal cardiac disease do well
1% risk of endocarditis, dissection, heart failure
10% risk if aortic diameter is >40mm (>47 repair recommended)
beta blockers
consult with anesthesiology (dural ectasia could complicate epidural)
15% prematurity (20-32 weeks)due to PRM, cervical insufficiency, or maternal cardiac status
no increased fetal morbidity
What conditions would be included on a DDx for symptoms of Marfan syndrome?
Loeys-Deitz Congenital Contractural Arachnodactyly Familial or Hereditary Thoracic Artery Aneurysms and Disection (FTAAD or HTAD) Shprintzen-Goldberg Homocystenuria
What symptoms over lap between Marfan Syndrome and Homocystenuria?
ectopia lentis (homocystenuria is downslanting)
myopia
tendency to thrombosis
failure to thrive in newborns and/or developmental delay
tall stature with long, thin limbs and fingers
chest deformaties
scoliosis
What symptoms are associated with Loeys-Dietz Syndrome 1?
facial dysmporphism cleft palate bifid uvula cranisynostosis micrognathia
What symptoms are associated with Loeys-Deitz Syndrome?
EDS-like with bruising, poor scaring, joint laxity, and visceral rupture
newer phenotypic findings include facial milia, IBD, eosinophilic esophagitis
What symptoms are associated with Loeys-Deitz Syndrome in general?
aortic root aneurysm (common, early rupture at small diameters- 50% will have at other locations)
bicuspid aortic valve
arterial tortuosity (head and neck vessels)
dissection of vessels in thoracic region
average age at first surgery:13 y/o
average age at death: 26 y/o
increased risk of uterine rupture in pregnancy
What is Loeys-Deitz syndrome?
AD 75% new mutations TGFBR1 and TGFBR2 (55-60%) SMAD3 (osteoarthritis) TGFB2 and TGFB3 (milder)
What other conditions result from mutations in FBN1?
Weill Marchesani
Geleophysical dysplasia
Acrommicric dysplasia
List the disorders of collagen production and assembly and which type of collagen the affect.
Type I: Osteogenesis Imperfecta
Type II, IX, and XI: Stickler Syndrome
Type III: Vascular Ehler’s Danlose Syndrome
Type V: Classic Ehler’s Danlose Syndrome
What is Ehler’s Danlose Syndrome?
mostly AD
heterogenous group of disorders
best known subtypes include classic, hypermobile, adn vascular
What are the symptoms consistent across all subtypes of Ehler’s Danlose Syndrome?
skin hyperextensibility
joint hypermobility
connective tissue fragility
Describe the vascular subtype of EDS.
COL3A1 gene (encodes type III procollagen homotrimer in skin, blood vessels, and organs)
accounts for 4% of all EDS
most severe with high mortality
hard to diagnose without a genetic test
mean age of death is 48y/o presenting with to acute abdomen, retroperitoneal hemorrhage, and sudden collapse/shock
What are the major clinical diagnostic criteria for vascular EDS?
arterial rupture (young age) intestinal rupture uterine rupture family history of vascular EDS with documented mutation AV fistula (carotid-cavernous sinus)
What are the minor clinical diagnostic criteria for vascular EDS?
skin bruising/translucency facial appearance acrogeria hypermobility of small joints tendon/muscle rupture pneumothorax joint subluxation/dislocations CHD/club foot varicose veins gingival recession keratoconus
What other symptoms are present with vascular EDS?
mitral valve prolapse
strokes and progressively dilating aneurysms (less common)
GI issues (sigmoid perforations)
uterine rupture in perinatal period
pregnancy related complications
inguinal hernias, pneumothorax, and/or joint dislocations in childhood
How is vascular EDS managed?
avoid contact/competitive sports and isomeric exercise
anticoagulation contraindicated
DON’T stick needles in arteries
elective surgery increases complication rates
beta blockers or celiprolol questionable
possible surveillance with MRA/MRI
medical alert bracelets
11.5% maternal mortality (due to uterine rupture)
Describe classic EDS.
COL5A1/COL5A2 mutants resulting in type V collagen defect (90% of patients)
complete lack of Tenascin XB (TNX gene)
How is classic EDS diagnosed?
skin hyperextensibility and atrophic scarring with joint hypermobility and/or at least three of the following (minor criteria): family history bruising soft skin fragility hernia
Describe the hypermobile form of EDS.
clinical diagnosis ONLY because basically no genes
criteria is the Beighton scale which requires >5.. plus two of the following:
5+ symmetric feature
positive family history
musculoskeletal (pain and medically confirmed dislocations/instability)
EXCLUDES:
unusual fragility/rheumatological or other alternative diagnosis such as neuromuscular, etc
What disorders other than EDS affect the ascending aorta?
FTAAD (Familial aortic aneurysm and dissection)
What kinds of testing is available for EDS?
biochemical/genetic testing with skin fibroblasts (secrete connective tissue proteins so you can quantitatively and qualitatively assay for abnormal collagen or fibrillin by electrophoresis- this is rare) or NGS (COL5A1/COL5A2, COL3A1, COL1A1/COL1A2 or single gene testing with del/dup)
What is Osteogenesis Imperfecta?
AD (collagen-related subtypes) AR (non-collagen subtypes- only 10-15%)
COL1A1 or COL1A2
abnormal collagen microfibril assembly
4 common subtypes
List the most common collagen-related subtypes of Osteogenesis Imperfecta.
Type I (50%): blue sclera, normal height, fractures, hearing loss, DI rare Type II (severe): perinatal lethality, limb defects, blue-grey sclera, soft calvarium, multiple fractures Type III (severe): fractures, deformities, early hearing loss, DI, progressive Type IV: normal sclera, DI common, adult hearing loss, milder than III
How is Osteogenesis Imperfecta managed?
orthopedic PT psychosocial bisphosphinates (to improve mineralization) screenings for hearing loss dental screenings
Describe the continuum of syndromes/phenotypes for Type II Collagenopathies.
skeletal dysplasia (severe disproportionate short stature)
ocular (retinal and myopia)
hearing loss (mixed)
orofacial (flat facies, Pierre Robin sequence, cleft palate, laryngomalacia)
List the Type II Collagenopathies.
Achondrogenesis type II (lethal)
Kneist, SEDC (severe)
SED, Stickler type I (intermediate)
SED with arthritis (mild)
What is Stickler Syndrome?
COL2A1 (80-90%) and COL11A1 (10-20%) results in ocular, mild hearing loss, joint involvement rare COL11A2 (non-ocular form) and COL9A1/COL9A2 (recessive forms)
What symptoms are associated with Stickler Syndrome?
eye (early onset cataracts, vitreous anomaly, retinal detachment, myopia, >3D)
craniofacial (depressed nasal bridge, bifid uvula or cleft palate, Robin sequence)
hearing (sensorineural/conductive hearing loss)
joint disease (hypermobility, osteoarthritis, spondyloepiphyseal dysplasia)
List the perinatal lethal skeletal dysplasias.
FGFR3 (Thanatophoric dysplasia- AD)
Type 2 Collagenopathy (Achondrogenesis II, hypochondrogenesis- AD)
Sulfation disorder (achondrogenesis 1B- AR)
Short Rib-Polydactyly syndromes (AR)
Osteogenesis Imperfecta Type 2 (AD)
Campomelia dysplasia (AD) or XY DSD
What is Thanatophoric Dysplasia?
TD1 or TD2
most common neonatal lethal dysplasia
What phenotype is associated with Thanatophoric Dysplasia?
shortened and or bowed limbs platyspondyly narrow chest with protuberant abdomen short ribs macrocrania with frontal bossing +/- hydrocephalus cloverleaf skull polyhydramnios redundant, thickened soft tissues CNS abnormalities (mild ventriculomegaly, posterior fossa hypoplasia, temporal lobe abnormalities)
What is Achondroplasia?
AD most common non-lethal dysplasia FGFR3 mutations fully penetrant 80% de novo paternal origin homozygous cases are lethal but can have compound hets with other genes
What features at birth are indicative of Achondroplasia?
macrocephally sleep apnea frontal bossing cervical cranial junction rhizomelia and other segments trident hands (splaying of digits 3 and 4) lordosis, bowing hydrocephalus spinal stenosis abnormal radiological findings
List the FGFR3 Related Disorders.
Hypochondroplasia Thanatopheric dysplasia Craniosynostosis SADDAN Homozygous Achondroplasia mutations
What are common features of Skeletal Ciliopathies?
narrow chest
short limbs
short ribs
polydactyly
List examples of Skeletal Ciliopathies.
Cranioectodermal dysplasia
Ellis van Creveid
What are Skeletal Ciliopathies?
AR
defects in non-motile cilia (primary cilia)
